11-deoxyprostaglandin derivatives and process therefor

ABSTRACT

1. A PROCESS FOR PREPARING A COMPOUND OF FORMULA I   1-(O=),2-(R-OOC-(CH2)P-(A)-CH2-),3-(H3C-(C)-CH(-O-R1)-   (B)-),4-R2-CYCLOPENTANE   IN WHICH (A) IS CH2CH2, CIS CH=CH OR C$C, P IS AN INTEGER FROM 2 TO 4, (B) IS TRANS CH=CH, (C) IS EITHER (CH2)Q WHEREIN Q IS AN INTEGER FROM 1 TO 6 OR CIS CH2CH=CH8CH2)R WHEREIN R IS AN INTEGER FROM 0 TO 3, R AND R1 IS EACH HYDROGEN AND R2 IS HYDROGEN, LOWER ALKYL OR CH2 OR3 WHEREIN R3 IS HYDROGEN WHICH COMPRISES SUBJECTING A COMPOUND OF FORMULA II   1,1-DI(R4-OOC-),2-(H3C-(C)-CH(-O-R5)-CH=CH-),3-R2-   CYCLOPROPANE   IN WHICH R2 IS HYDROGEN, LOWER ALKYL OR CH2OR3 IN WHICH R3 IS LOWER ALKANOYL, R4 IS LOWER ALKYL, R5 IS HYDROGEN OR TETRAHYDROPYRAN-2-YL AND (C) IS AS DEFINED HEREIN TO A BASE CATALYZED CONDENSATION AT A TEMPERATURE OF 100* TO 150* C. FOR 30 MINUTES TO THREE HOURS IN THE PRESENCE OF, AS THE BASE, AN ALKALI METAL ALKOXIDE OR AN ALKALI METAL HYDROXIDE WITH APPROXIMATELY AN EQUIMOLAR AMOUNT OF A TRIESTER OF FORMULA III   R-OOC-(CH2)P-(A)-CH2-CH(-COO-R6)2   IN WHICH R AND R6 ARE LOWER ALKYL AND (A) AND P ARE AS DEFINED HEREIN TO YIELD THE CORRESPONDING CYCLOPENTANONETRIESTER SELECTED FROM THE GROUP CONSISTING OF FORMULA IVA AND FORMULA IVB   1-(O=),2-(R6-OOC-),2-(R-OOC-(CH2)P-(A)-CH2-),3-(H3C-(C)-   CH(-O-R5)-CH=CH-),4-R7,5-(R-OOC-)-CYCLOPENTANE   1,6-DI(O=),4-(H3C-(C)-CH(-O-R5)-CH=CH-),5-(R-OOC-(CH2)P-   (A)-CH2-),5-(R6-OOC-)-TETRAHYDRO-1H-CYCLOPENTA(C)FURAN   IN WHICH (A), (C), P, R4, R5 AND R6 ARE AS DEFINED HEREIN, R IS LOWER ALKYL AND R7 IS HYDROGEN OR LOWER ALKYL, SAID CYCLOPENTANONETRIESTER OF FORMULA IVA BEING OBTAINED WHEN R2 OF THE COMPOUND OF FORMULA II IS HYDROGEN OR LOWER ALKYL AND SAID CYCLOPENTANONETRIESTER OF FORMULA IVB BEING OBTAINED WHEN R2 OF THE COMPOUND OF FORMULA II IS CH2 OR3 IN WHICH R3 IS LOWER ALKANOYL; IN THE INSTANCE WHEN R5 OF THE CYCLOPENTANONETRIESTER IS TETRAHYDROPYRAN-2-YL SUBJECTING THE CYCLOPENTANONETRIESTER TO TREATING WITH AN ACID IN AN INERT SOLVENT IN THE PRESENCE OF WATER TO REMOVE THE TETRAHYDROPYRAN-2-YL PROTECTING GROUP TO OBTAIN THE CORRESPONDING CYCLOPENTANONETRIESTER IN WHICH R5 IS HYDROGEN, AND THEREAFTER TREATING THE INSTANT CYCLOPENTANONETRIESTER INTERMEDIATE WITH AN ALKALI METAL HYDROXIDE TO GIVE THE CORRESPONDING COMPOUND OF FORMULA I IN WHICH R AND R1 ARE HYDROGEN AND R2 IS HYDROGEN, LOWER ALKYL OR CH2OR3 WHEREIN R3 IS HYDROGEN.

3,849,474 ll-DEOXYPROSTAGLANDIN DERIVATIVES AND PROCESS THEREFORNednmparambil A. Abraham, Dollard des Ormeaux,

Jehan F. Bagli, Kirkland, and Tibor Bogri, Montreal,

Quebec, Canada, assignors to Ayerst, McKenna and Harrison Limited, VilleSt. Laurent, Quebec, Canada No Drawing. Filed Mar. 27, 1972, Ser. No.238,650

Int. Cl. C07c 11/36 US. Cl. 260-468 D 10 Claims ABSTRACT OF THEDISCLOSURE A process for preparing ll-deoxyprostaglandin E E and E andanalogs thereof is realized by treating an appropriate di(lowe-r)alkyl3-(optionally substituted)- 2-formylcyc1opropane-1,1-dicarboxy1ate withan ylid prepared from a Wittig reagent of formula in which Alk is analkyl containing one to three carbon atoms and is either (CH wherein qis an integer from 1 to 6 or cis CH CH=OI-I(CH wherein r is an integerfrom 0 to 3 to obtain the corresponding compound of formula:

R4000 ooon in which R is hydrogen, lower 'alkyl or CH OR wherein R islower alkanoyl, R is lower alkyl and (c) is as defined here'in. Thelatter compound is reduced with an alkali metal borohydride to yield thecorresponding alcohol derivative. Condensation of this alcoholderivative or preferably its corresponding tetrahydropyran-Z-yl etherderivative with a triester of formula in which R and R are lower alkyl,'(a) is'CH OH cis CH=CH or CEO and p is an integer from 2 to 4, givesthe corresponding cyclopentanonetriester of formula in which (a), '(c),p, R, R and R are as defined herein, R is hydrogen ortetrahydropyran-Z-yl, respectively, and R is hydrogen or lower alkyl;the 'lactonized form of the cyclopentanonetriester being obtained fromsaid alcohol derivative in which R is CH OR wherein R is lower alkanoyl.In the instance when R is tetrahydropyran-Z-yl thecyclopentanonetriester is treated with. an-acid to give thecorresponding compound in which R is hydrogen. The instant compound isthen treated with a base under aqueous conditions, followed by optionalesterification United States Patent 0 and acylation to give the desiredll-deoxyprostaglandin derivatives of formula BACKGROUND OF THEINVENTION 1. Field of Invention This invention relates to prostaglandinderivatives.

7 More particularly this invention relates to derivatives of9,15-dioxygenated prostanoic acid and homologs thereof, to novel methodsfor producing these derivatives and to novel chemical intermediatesuseful in these methods.

2. Description of the Prior Art Prostaglandins are naturally occurringC-20 fatty acids. The basic prostaglandin molecule contains acyclopentane nucleus with two side chains. The chemistry andpharmacological effects of the prostaglandins have been the subject ofseveral recent reviews; for example, see E. W. Horton, Physiol. Rev.,49, 122 (1969), D. F. Bagli in Annual Reports in Medicinal Chemistry,1969, C. K. Cain, Ed., Academic Press, New York and London, 1970', p.170, and J. E. Pike in Progress in the Chemistry of Organic NaturalProducts, Vol. 28, W. Herz, er al. Eds, Springer Verlag, New York, 1970,p. 313.

The pharmacological effects knoWn to be associated with theprostaglandins relate to the reproductive, cardiovascular, respiratory,gastrointestinal land renal systems.

Due to the increasing interest in these natural products a ratherextensive effort has been given recently to the synthesis ofprostaglandins and their analogs. Included among these synthesis areseveral synthetic methods for the preparation of 9,15-dioxygenatedderivatives of prostanoic or prost-13-enoic ac'ids. For example, thesynthesis of the first pharmacologically active 9,15-dioxygenatedprostanoic acid derivative, 95,15i-dihydroxyprost-13-enoic acid(ll-desoxyprostaglandin F was reported in detail by I. -F. Bagli, T.B-o-gri and R. Deg-henghi, Tetrahedron Letters, 465 (1966). Asignificant simplification and modification of that process wasdescribed by Bagli and Bogri in US. Pat. No. 3,455,992, issued July 15,1969, whereby 9,15-dihydroxyprost-13-enoic acid as well as homologsthereof were obtained, see also Bagli and Bogri, Tetrahedron Letters, '5(1967).

A further improvement in the synthesis of 9,15-dioxygenated derivativesof prostanoic acid has been described by Bagli and Bogri in TetrahedronLetters, 1639 (1969), and German Oifenlegungsschrift No. 1,953,232,published Apr- 30, 1970. This latter synthesis gave9,15-dioxoprostano'ic acid methyl ester and homologs thereof, from whicha number of other 9,15-dioxygenated derivatives of prostanoic acid andof homologs thereof were prepared by conventional means.

A synthesis of 9,15-dioxygenated prostanoic and prost- 13-enoic acidderivatives from 9,11,15-trioxygen'ated derivatives is reported inBritish Patent Specification No. 1,097,533, published Jan. 3, 1968.Among the derivatives prepared by this synthesis are the compounds offormula I of this invention in which (a) is CH CH (b) is trans 3 CH=CH,p is the integer 3, (c) is (CH wherein q is the integer 4, R is hydrogenor lower alkyl and R and R are hydrogen.

It is particularly noteworthy that the synthetic 9,15- dioxygenatedprostanoic acid derivatives described above possess a number of thebiological activities of the natural compounds although they lack thell-hydroxyl of the latter.

Notwithstanding the fact that many of the syntheses reported to date areoutstanding achievements, it is the purpose of the present invention toprovide an efiicient, economical process that affords one or more of thefollowing advantages over the earlier processes: (a) simplicity ofoperation, (b) versatility of its application to the preparation ofll-deoxy PGE PGE and PGE analogs and ll-substituted derivatives thereof,applicability to the preparation of higher and lower homologs thereof,and (d) the final products of this invention are readily reduced byknown methods to the corresponding derivatives in the PGE series.

The present invention relates to an entirely new approach for thesynthesis of 9,15-dioxygenated prostanoic acid derivatives which isunrelated to any of the above processes. The basis for this new approachis the unexpected discovery that an appropriately substituted dialkylcyclopropane-1,1-dicarboxylate derivative condenses with anappropriately substituted dialkyl malonate derivative to give thecorresponding cyclopentan 2 one 1,3-dicarboxylate derivative. Thelatter, upon appropriate transformations, thereafter is converted to thecompounds of this invention, viz., cyclopentan-l-ones suitablysubstituted at positions 2 and 3 in a trans relationship with carbonside chains bearing the functional groups and the requisite degree ofunsaturation analagous to the prostaglandin molecule, see the stepsII+III IV I described hereinafter.

Although R. W. Kierstead et al., J. Chem. Soc., 3616 (1952) and R.Giuliano et al., Ann. Chim. (Rome), 50, 750 (1960), Chem. Abstr. 55,3463 (1961) previously have condensed cyclopropane 1,1 dicarboxylatederivatives with dialkyl malonate or substituted derivatives thereof,the process of the present invention is readily distinguished from theprior art because decarboxylation of the intermediate tricarboxylateobtained by the process of this invention gives 2,3-disubstitutedcyclopentan-l-one derivatives in which the side chains attached intrans-relationship to position 2 and 3 both carry functional groups,while the processes of the prior art were not capable of allowing theintroduction of such side chains.

SUMMARY OF THE INVENTION The prostaglandin derivatives of this inventionmay be represented by general formula I:

3 b) CH- (0) CH:

in which (a) is CH CH cis CH=CH or CEC, p is an integer from 2 to 4, (b)is trans CH=CH, (c) is either (CH wherein q is an integer from 1 to 6 orcis wherein r is an integer from 0 to 3, R is hydrogen or lower alkyl, Ris hydrogen or lower alkanoyl and R is hydrogen, lower alkyl or CH ORwherein R is hydrogen or lower alkanoyl, provided that R is the same asR The prostaglandin derivatives of this invention may be prepared by aprocess involving a series of key steps which are representedschematically in the following manner:

R OOC\ COOR COOR 0 ll CH1 (a) (CH1) p C O O R CH- (C) CH; O 2

IVb.

in which (a), (c) and p are as defined hereinbefore, R is lower alkyl, Ris hydrogen, lower alkyl or CH OR in which R is lower alkanoyl, R islower alkyl and R is hydrogen or a radical suitable for protecting ahydroxyl, preferably tetrahydropyran 2 yl or tert butyl, R is loweralkyl and R is hydrogen or lower alkyl.

In the preceding process the compound of formula His subjected to a basecatalyzed condensation with the triester of formula III to yield thecyclopentanonetriester, of formula IV or IVb. The lactonized form of thecyclopentanonetriester, compound IVb, is obtained in this process when Rof compound II is CH OR wherein R is lower alkanoyl. In the instancewhen R of the cyclopentanonetriester of formulae IVa or IVb is aprotecting radical, as defined hereinbefore, said cyclopentanonetriesteris then treated with a suitable acid to remove the protecting radicalwhereby the corresponding cyclopentanonetriester of formulae IVa or IVbin which R is H is obtained. The instant intermediate of formulae IVa orIVb is then treated with a base under aqueous conditions to give thecorresponding compound of formula I in which R is hydrogen. Thereafterand if desired the latter compound is esterified to give thecorresponding compound of formula I in which R is lower alkyl and ifdesired said latter compounds of formula I in which R is hydrogen orlower alkyl is acylated to give the corresponding compound of formula Iin which R and R are lower alkanoyl.

According to a further feature of this invention a process for thepreparation of compounds of formula II comprises the treatment of analdehyde of formula V.

R 000 COOR R2 CHO V in which R is hydrogen, lower alkyl or CH OR inwhich R is lower alkanoyl and R is lower alkyl, with an ylid preparedfrom a Wittig reagent of formula (AlkO) POCH CO-(c)CH in which (c) is asdefined in the first instance and Alk is an alkyl containing one tothree carbons, in the presence of a suitable base to obtain a compoundof formula VI R 000 COOR CO(c)CHa VI in which R R and (c) are as definedabove, reducing the latter compound with an alkali metal borohydride toobtain the compounds of formula II in which R is hydrogen and if desiredconverting the latter compound to the corresponding compounds of formulaII in which R is a radical suitable for protecting a hydroxyl,preferably a tetrahydropyran-Z-yl.

Still another feature of this invention is that the process describedherein leads to the compounds of formula I in which the two side chainsare in the trans configuration characteristic for the naturalprostaglandins.

DETAILS OF THE INVENTION The term lower alkyl as used hereincontemplates straight or branched chain alkyl groups containing from oneto three carbon atoms and straight alkyl chains containing from four tosix carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl,pentyl and hexyl.

The term lower alkanoyl as used herein contemplates straight or branchedchain alkanoyl radicals containing from two to five carbon atoms andincludes acetyl, propionyl, butyryl, isobutyryl, pentancyl and pivaloyl.

The compounds of formula I possess interesting pharmacologicalproperties when tested in standard pharmacological tests. In particular,they have been found to possess hypotensive, antihypertensive,bronchospasmolytic, and gastic acid secretion inhibiting properties,which make them useful in the treatment of conditions associ ated withhigh blood pressure, in the treatment of asthmatic conditions and in thetreatment of pathological conditions associated with excessive secretionof gastic acid such as, for example peptic ulcer. In addition, thecompound of this invention inhibits the aggregation of platelets andpromote the disaggregation of aggregated platelets, and are useful asagents for the prevention and treatment of thrombosis.

More particularly, these compounds, when tested in a modification of thetests for determining hypotensive activities described in ScreeningMethods in Pharmacology, Academic Press, New York and London, 1965, page146, using the cat in urethane-chloralose anasthesia as the test animaland measuring mean arterial blood pressure before and after intravenousadministration of the compounds, have exhibited utility as hypotensiveagents. When tested in the renal hypertensive rat prepared by the methodof A. Grollman described in Proc. Soc. Exp. Biol. Med., 7, 102 (1954),and measuring blood pressure by the method described by I-I. Kersten, J.Lab. Clin. Med, 32 1090 (1947), they have exhibited utility asantihypertensive agents.

Moreover, the compounds of this invention, when tested in a modificationof the test method described by A. K. Armitage, et al., Brit. J.Pharmacol., 16 59 (1961), have been found to alleviate bronchospasms,and are useful as bronchospasmolytic agents.

Furthermore, the compounds of this invention, when administered to ratsin the test method described by H. Shay, et al., GastroenteroL, 26 906(1954), have been found to inhibit the secretion of gastic acid, and areuseful as agents inhibiting the secretion of gastic acid.

In addition, the compounds of this invention, when tested in amodification of the test method described by G. V. R. Born, Nature, 194,927 (1962), using the aggregometer manufactured by Bryston ManufacturingLimited, Rexdale, Ontario, Canada, have been shown to inhibit theaggregation of platelets and to promote the disaggregation of aggregatedplatelets, and are useful as agents for the prevention and treatment ofthrombosis.

When the compounds of this invention are employed as hypotensive oranti-hypertensive agents, as agents in hibiting gastic acid secretion inWarm-blooded animals, for example, in cats or rats, as agents for theprevention or treatment of thrombosis, or as bronchospasmolytic agents,alone or in combination with pharmacologically acceptable carriers,their proportions are determined by their solubilities, by the chosenroute of administration, and by standard biological practice. Thecompounds of this invention may be administered orally in solid formcontaining such excipients as starch, lactose, sucrose, certain types ofclay, and flavouring and coating agents. However, they are preferablyadministered parenterally in the form of sterile solutions thereof whichmay also contain other solutes, for example, sufiicient sodium chlorideor glucose to make the solution isotonic. For use as bronchospasmolyticagents, the compounds of this invention are preferably administered asaerosols.

The dosages of the present hypotensive, antihypertensive, gastric acidsecretion inhibiting, or bronchospasmolytic agents, or agents for theprevention and treatment of thrombosis will vary with the forms ofadministration and the particular hosts under treatment. Generally,treatments are initiated with small dosages substantially less than theoptimum doses of the compounds. Thereafter, the dosages are increased bysmall increments until the optimum effects under the circumstances arereached. In general, the compounds of this invention are most desirablyadministered at a concentration level that will generally affordeffective results without causing any harmful or deleterious sideeffects and preferably at a level that is in a range of from about 0.1mg. to about 10.0 mg. per kilo, although as aforementioned variationswill occur. However, a dosage level that is in range of from about 0.5mg. to about 5 mg. per kilo is most desirably employed in order toachieve effective results. When administering the compounds of thisinvention as aerosols the liquid to be nebulized, for example, water,ethyl alcohol, dichlorotetrafluoroethane and dichlorodifluoromethane,contains preferably from 0.005-0.05 percent of the acid, or a non-toxicalkali metal, ammonium or amine salt thereof, or ester of formula I.

Furthermore, when the compounds of this invention are tested by themethod of A. P. Labhsetwar, Nature, 230, 588 (1971) whereby the compoundis given subcutaneously on a daily basis to mated hamsters on days 4, 5and 6 of pregnancy, thereafter the animals being sacrificed on day 7 ofpregnancy and the number of abortions counted, the compounds are shownto have abortifacient properties. Also the compounds of this inventionare useful for inducing labor in pregnant animals at or near term. Whenthe compounds of this invention are employed as agents for abortion orfor inducing labor, the compound may be infused intravenously at a dose0.01 to 500 mg./kg. per minute until the desired effect is obtained.

Process As noted hereinbefore the preparation of the compounds of thisinvention involve the base catalyzed condensation of a compound offormula II in which (c), R and R are as defined in the first instanceand R is hydrogen, lower alkyl, or CH OR in which R is lower alkanoylwith a triester of formula III in which (a) and p are as defined in thefirst instance and R is lower alkyl.

The compound of formula II for this key reaction prepared as follows:

A di(lower)alkylbromomalonate, for example, dirnethylbromomalonate,prepared by using the procedure for diethyl bromomalonate, OrganicSyntheses, Collect, Vol. 1, 2nd ed., A. H. Blatt, Ed. John Wiley & Sons,New York, N.Y., 1956, p. 245, is condensed in the presence of an alkalimetal lower alkoxide in a lower alkanol, preferably sodium methoxide inmethanol, with acrolein; an u,/3-unsaturated aldehyde of formula (loweralkyl) -CH=CH-CHO (see Rodds Chemistry of the Carbon Compounds, S.Coffey, Ed., Vol. 1c, 2nd Ed. pp. 48-51), for example, crotonaldehyde,2-hexenal, and the like; or a -(lower alkanoyloxy)crotonaldehyde,preferably 7- acetoxycrotonaldehyde (prepared by treating'y-acetoxycrotonaldehyde diacetate, H. Schmid and E. Grob, Helv, Chim.Acta 32, 77 (1949), with one equivalent of water in a lower alkanol); toyield a cyclopropanealdehyde derivative of formula V, i.e. adi(lower)alkyl 2-formylcyclopropane 1,1 dicarboxylate, the corresponding3- lower alkyl analog or the corresponding 3-(lower alkanoyloxymethyl)analog, respectively. The reaction conditions described by D. T. Warner,J. Organic Chemistry, 24, 1536 (1959) for the preparation of thecyclopropanealdehyde derivatives, diethyl 2-formylcyclopropane-1,1-dicarboxylate and its corresponding 3-methyl analog,are convenient and quite satisfactory for this condensation.

The cyclopropanealdehyde derivative of formula V so obtained is thentreated with the ylid prepared from a Wittig reagent, of the formula inwhich (c) is as defined hereinbefore, and Alk is an alkyl containingfrom 1 to 3 carbon atoms, preferably a dimethyl 2-oxoalkylphosphonate,in the presence of an alkali metal hydride, preferably sodium hydride,and in an aprotic solvent, preferably dimethoxyethane. Acidificationwith an aqueous acid, preferably aqueous acetic acid, extraction with awater-immiscible solvent, preferably diethyl ether, followed by washing,drying and evaporation of the latter, yields the corresponding compoundof formula VI in which R is hydrogen, lower alkyl or CH OR in which R islower alkanoyloxy.

The requisite Witting reagents are either known, for example, dimethyl2-oxoheptylphosphonate, E. J. Corey, et al., J. Am. Chem. Soc., 90, 3247(1968) or they may be prepared by the method of E. J. Coreyand G. T.Kwiatkowski, J. Am. Chem. Sc., 88, 5654 (1966) using the appropriatelower alkyl alkanoate or lower alkyl alkenoate and di(lower)alkyla-lithiomethanephosphonate.

More specifically, the treatment of the cyclopropanealdehyde derivativeof formula V with the ylid is performed in the following manner. Asolution of the Wittig reagent in about 5 to parts of an aproticsolvent, preferably dimethoxyethane, is added slowly under a blanket ofnitrogen to a stirred suspension of approximately one equivalent of analkali metal hydride, preferably sodium hydride, in approximately 150parts of the aprotic solvent and stirring is continued at roomtemperature for a period of time of from 10 to 60 minutes, preferablyfor about 30 minutes. To the resulting solution of the correspondingylid there is slowly added a solution of approximately three quarters toone equivalent, preferably about 0.85 equivalent, of the appropriatecyclopropanealdehyde derivative described above in about 5-10 parts,preferably about 8 parts of an aprotic solvent, preferablydimethoxyethane. The addition is carried out at room temperature over aperiod of time of from 5 to 30 minutes, preferably about 10 minutes, andstirring is continued for another 10 to 60 minutes, preferably for about30 minutes. Acidification with an aqueous acid, preferably aqueousacetic acid, followed by extraction with a water-immiscible solvent,preferably diethyl ether, washing and drying of the extracts,evaporation of the solvent, and chromatography of the residue on silicagel yields the corresponding compound of formula VI in which (0) is asdefined hereinbefore, R is hydrogen, lower alkyl or CH2OR3 wherein R islower alkanoyloxy and R is lower alkyl.

As an alternative to the above preferred procedure, the compounds offormula VI in which R is hydrogen and (c) is (CH wherein q is an integerfrom 1 to 6 are prepared in the following manner: A chlorovinyl ketoneof formula ClCH=CHCO(CH CH in which n is an integer from 1 to 6,prepared by the general procedure described for the preparation of1-chloro-6-methyl-1-hepten- 3-one in Organic Syntheses, 32, 27 (1952),is converted to its corresponding di(lower)alkylaminovinyl ketone bytreatment with an excess, for example two to five molar equivalents, ofa di(lower)alkylamine, preferably 40% aqueous dimethylamine at roomtemperature for minutes. The aminovinyl ketone is then reacted with avinyl magnesium halide, preferably vinyl magnesium bromide, in an inertsolvent, preferably dry tetrahydrofuran or ether. Preferred conditionsfor this reaction include a temperature range from room temperature tothe boiling point of the mixture and a reaction time of 30 minutes tofour hours. In this manner the dienone of formula CH :CI-ICHCHCO(CH),,CH in which n is an integer from 1 to 6 is obtained.

The same dienone is obtained also by treating the aminovinyl ketone,described above with lithium acetylide or an acetylene Grignard reagent,for example, ethynyl magnesium bromide or preferably lithiumacetylideethylenediamine complex, in an inert solvent, preferablydioxane, under essentially the same conditions described above for thereaction of a vinyl magnesium halide whereby said aminovinyl ketoneyields a compound of formula (lower alkyl) NCH(CECH)CH CO(CH ),,CH inwhich n is an integer from 1 to 6. Treatment of the latter compound withan excess of acid, for example, 1.2 to 2.5 molar equivalents ofhydrochloric, sulfuric or preferably p-toluenesulfonic acid, in an inertsolvent, for example, methanol or tetrahydrofuran, to effect theelimination of one molecule of di(lower)alkyl amine, followed byhydrogenation of the corresponding alkenynone product of formulaCHECCH=CH=CHCO(CH ),,CH in which n is as described above, obtainedtherefrom, in the presence of Lindlar catalyst affords the dienone offormula CH =CHCH=CHCO(CH ),,CH described above.

The latter dienone is now treated with a di(lower)alkyl bromomalonate,described above, in the presence of an alkali metal lower alkoxide toyield the desired compound of formula VI in which R is hydrogen, R islower alkyl and (c) is (CH wherein q is an integer from 1 to 6. Morespecifically this reaction is effected by adding simultaneously asolution of the dienone in a lower alkanol, for example, ethanol, and asolution of about one equivalent of an alkali metal lower alkoxide, forexample, sodium ethoxide, in the same lower alkanol as above, to anagitated solution of approximately one equivalent of the di(lower)alkylbromomalonate, for example, diethyl bromomalonate, in the same loweralkanol described above. The temperature during addition may range from20 to 60 C., preferably 0 to 20 C. After completion of the addition, themixture is stirred for about three hours at the same temperature then atroom temperature for a further eight to 24 hours. Thereafter the mixtureis neutralized with acid, preferably acetic acid, the precipitatedalkali metal bromide separated by filtration, and the reaction mixtureconcentrated. The residue is purified on silica gel to yield the desiredcompound of formula VI.

Thereafter, the compound of formula VI in which (a) is as defined in thefirst instance, R is hydrogen, lower alkyl or CH OR wherein R is loweralkanoyloxy and R is lower alkyl is reduced with an alkali metalborohydride, potassium borohydride or preferably sodium borohydride, inan inert solvent to yield a mixture of epimers of the desired compoundof formula II in which R is hydrogen. The epimers result from theassymetric center at the carbon to which the secondary alcohol isattached. The mixture of epimers need not be separated at this stage. Inpractice it has been found more convenient to continue the process withthe mixture of epimers and if desired separate the resulting epimers ofcompounds of formula I.

Thereafter and if desired, the compound of formula II in which R ishydrogen is converted to the corresponding compound of formula II inwhich R is a radical suitable for protecting a hydroxyl, preferably atetrahydropyran-2- yl which is readily formed by treating said lattercompound with dihydropyran in the presence of an acid catalyst; forinstance, p-toluenesulfonic acid is preferred. Sulfuric acid is also asuitable catalyst for this purpose.

The triester of formula III for the above key reaction is prepared inthe following manner:

9 The triester of formula III in which (a) is CEC, noted above, isprepared by a process which is represented schematically in thefollowing manner:

L OCPh CH BI(GH7)9C1 VII. VIII.

L CHzC C (0112)::

HOCH C CEKCHD CI HOCHgC CH(CHz)pCN X. XI.

HOCH C CUJHD JCOOH BrCH2C=C(CHz) COOH XII. XIII;

in which p is as defined in the first instance and R is lower alkyl.

With reference to the preceding process propargyl alcoholtetrahydropyran 2-yl ether, described by R. G. Jones and M. J. Mann, J.Amer. Chem. Soc., 75, 4048 (1953), is condensed with a dihaloalkane offormula VIII to give the tetrahydropyranyl ether of formula IX accordingto the procedure of A. I. Rachlin, et al., J. Org. Chem., 26, 2688(1961), used to prepare l-[(tetrahydropyran-2-yl)oxy]-6-chloro-2-hexyne. The tetrahydropyranyl ether of formula IX ishydrolyzed, for example, with p-toluenesulfonic acid in aqueousmethanol, to its corresponding alcohol of formula X, see also theprocedure of Rachlin, cited above, for the preparation of6-chloro-2-hexyn-1-ol (X, p =3). The alcohol X is then treated withpotassium or sodium cyanide in a lower alkanol, preferably withpotassium cyanide in ethanol, at reflux temperature for eight to 24hours to give the cyanide XI. Subsequently a solution containing anexcess of potassium hydroxide in water is added to the reaction mixtureof the cyanide X and the resultant mixture is heated at reflux for afurther ten to 20 hours whereby the cyanide X is converted to thecorresponding hydroxyacid XII. The latter compound is then brominated bytreatment and phosphorus tribromide in ether solution in the presence ofa suitable proton acceptor, for example, pyridine, to yield thecorresponding bromoacid XIII, which is esterified with a lower alkanol,for example, methanol in the presence of a suitable acid catalyst, forexample, p-toluenesulfonic acid, to give the corresponding bromoester offormula XV.

Alternatively, the order of the latter two steps of bromination andesterification are reversed whereby the hydroxyacid XII is converted tothe bromoester of formula XV via the hydroxy ester XIV.

Optionally, the corresponding chloroester of the bromoester of formulaXV is prepared by the preceding process by replacing the dihaloalkane offormula VIII with its corresponding a-iodo-(w)-chloroalkane. Thechloroester so obtained is used in the same manner as described hereinfor said bromoester.

Thereafter the desired triester of formula III in which (a) is CEC isobtained by condensing the above bromoester of formula XV 'with adialkylmalonate, in the presence of an alkali metal alkoxide in a loweralkanol. More particularly, the condensation is performed by adding thedialkylmalonate portionwise to a solution of one equivalent of sodiummethoxide in methanol at a temperature of from 10 to 30 C., preferablyroom temperature. After stirring for about 10 to minutes, the reactionmixture is treated portionwise with one equivalent of the bromoester offormula XV followed by heating the reaction mixture at refluxtemperature for one to two hours. Thereafter, dilution of the mixturewith water, extraction with a water-immiscible solvent, preferablyether, washing and drying of the extract, followed by removal of thesolvent gives a residue, which on purification by distillation underreduced pressure gives the desired triester III in which (a) iS CEC.

The triesters of formula III in which (a) is cis CH=CH or CH CH areprepared by condensing the appropriate lower alkyl w-haloalkanoate witha dialkylmalonate in the same manner as just described for thepreparation of triester III in which (a) is C50. The appropriate loweralkyl w-haloalkanates, for this condensation are either known or areprepared by known methods; for example, by hydrogenation of thebromoesters of formula XV or its corresponding chloroester, see alsoRodds Chemistry of the Carbon Compounds, cited above, Vol. 1c, pp. 201-252.

Alternatively, the triester of formula III in which (a) is cis CH=CH isprepared by hydrogenation of the corresponding triester of formula IIIin which (a) is CEC, described above, in the presence of Lindlarcatalyst.

The compound of formula II and the triester of formula III, prepared asdescribed above, are now subjected to a base catalyzed condensation togive the cyclopentanonetriester of formulae IV a and IVb. Morespecifically, the condensation is performed in the presence of suitablebase, preferably an alkali metal alkoxide, for example, sodiummethoxide. Other suitable bases include sodium ethoxide, potassiumtert-butoxide, and sodium hydride. In particular, this condensation maybe conveniently effected by heating a mixture of about equimolar amountsof the compound of formula II and the triester III at to C., preferablyl35-140 C., for 30 minutes to three hours, preferably one hour. Thereaction mixture is then cooled, treated with saturated sodium chloridesolution neutralized with an acid, for example, acetic acid, andextracted with a water-immiscible solvent, for example, ether.Evaporation of the extract and purification of the residue bychromatography on silica gel yields the cyclopentanonetriester offormula IVa or IVb.

Although compounds of formula II in which R is either hydrogen or aprotecting radical as defined above undergo the above base catalyzedcondensation, it is preferable to use those compounds of formula IIhaving the protecting group. In the latter case following thecondensation the protecting group is then removed. More explicitly in apreferred embodiment the base catalyzed condensation is effected with acompound in which R is tetrahydropyran- 2-yl and thereafter thetetrahydropyran 2 yl protecting group is removed treating the resultingcyclopentanonetriester of formula IV (R =tetrahydropyran-2-y1) withacid, for example, hydrochloric acid, aqueous acetic acid or preferablyp-toluenesulfonic acid, in an inert solvent in the presence of water,preferably methanol-water (9:1).

The cyclopentanonetriester (IVa or IVb) is now treated with an alkalimetal hydroxide under aqueous conditions to give the compounds offormula I in which (a), (b), (c) and p are as defined in the firstinstance, R and R are hydrogen and R is hydrogen, lower alkyl or CH ORwherein R is hydrogen. Preferably this reaction is done by heating amixture of the cyclopentanonetriester with an alkali metal hydroxide,preferably sodium hydroxide or potassium hydroxide, under aqueousconditions at reflux temperature of the mixture for a period of 15minutes to three hours, preferably about one hour. Neutralization of thereaction mixture with acid, for example, 2N HCl, extraction with awater-immiscible solvent, for example, ether, and subsequent work up ofthe extract yields a mixture of epimers of compounds of formula I inwhich R and R are hydrogen and R is hydrogen, lower alkyl or CH OR Iwherein R is hydrogen. If desired the epimers may be convenientlyseparated at this stage by chroma tography on silica gel. Forconvenience the less polar epimer is designated epimer A and the morepolar, epimer B.

Thereafter and if desired the latter compounds are esterified with alower alkanol, for example, methanol, ethanol or propanol, in thepresence of an acid, for example, sulfuric acid, hydrochloric acid orpreferably perchloric acid, to give the corresponding ester compounds offormula I in which (a), (b), (c) and p are as defined in the firstinstance, R is lower alkyl, R is hydrogen and R is hydrogen, lower alkylor H oR wherein R is hydrogen.

Within this latter group of compounds of formula I is the compound,9-oxo l hydroxyprost 13 enoic acid methyl ester (I; (a) =CH CH (b)=transCH=CH, 11:3, (0) is (CH wherein q is the integer 4 and R, R and R =H).By means of spectroscopic evidence this particular prostaglandinderivative has been shown to be identical with the same compounddescribed in British Patent Specification No. 1,097,533, noted above.

Finally, if desired the above compounds of formula I in which R ishydrogen or lower alkyl are acylated by treatment with an appropriatelower alkanoic anhydride or lower alkanoic acid chloride in the presenceof pyridine to give the corresponding compounds of formula I in which(a), (b), (c) and p are as defined in the first instance, R is hydrogenor lower alkyl, R is lower alkanoyl and R is hydrogen, lower alkyl or CHC-R wherein R is lower alkanoyl.

The following examples illustrate further this invention.

EXAMPLE 1 Dimethyl 2-Formylcyclopropane-1,1-dicarboxylate (V, R =H and R=CH By following the procedure of D. T. Warner, cited above, used forpreparing diethyl 2-formylcyclopropane- 1,1-dicarboxylate from acroleinbut using equivalent amount of dimethylbromomalonate and methanolinstead of diethylbromomalonate and ethanol, respectively, the titlecompound, nmr (CDCl 61.98 (m, 2H), 2.80 (m, 1H), 3.79 (s, 6H), 8.82 (d,J=4' cps., 1H), is obtained.

In the same manner but replacing acrolein with an equivalent amount ofcrotonaldehyde, 2-pentenal, 2- hexenal or 'y-acetoxycrotonaldehyde, thefollowing compounds of formula V,

dimethyl 2-formyl-3-methylcyclopropane-1,1-

dimethyl 2-formyl-3-propylcyclopropane-1,1-

dicarboxylate,

dimethyl 3-(acetoxymethyl)-2-formylcyclopropane-1,1-

dicarboxylate are obtained, respectively.

Likewise the corresponding diethyl and dipropyl esters of the abovecompounds of formula V are obtained by the choice of appropriatestarting materials. For example, by using diethylbromomalonate, ethanoland 'y-acetoxycrotonaldehyde, diethyl3-(acetoxymethyl)-2-formylcyclopropane-1,1-dicarboxylate,

31;; 2730, 1730 cmf is obtained.

'y-Acetoxycrotonaldehyde is prepared by treating 'yacetoxycrotonaldehydediacetate, H. Schmid and E. Grob, Helv. Chem. Acta, 32, 77 (1949), withone equivalent of water in a lower alkanol, for example, ethanol.

EXAMPLE 2.

Dimethyl trans-2-(3-Oxo-l-octenyl)cyclopropane-1,1- dicarboxylate [V1, R==H, R =CH and (c)=(CH To 5.56 g. of a sodium hydride (NaH) suspension,rinsed with dry hexane, suspended in 400 ml. dry 1,2- dimethoxyethane isadded 27.4 g. of the Wittig reagent, dimethyl(2-oxoheptyl)phosphonate,in 400 ml. dry 1,2- dimethoxyethane. The reaction mixture is stirred atroom temperature till all NaH reacts to give the sodium salt (about 45minutes). A solution of 21.6 g. of dimethyl 2-formylcyclopropane-l,l-dicarboxylate (V, R =H and R =CH described inExample 1, in 350 ml. dry 1,2- dimethoxyethane is added and the mixtureis heated at C. for /2 hr.; cooled, and acetic acid is added to renderthe mixture substantially neutral. After diluting with water the mixtureis extracted with ether. The extract is washed with water, dried (MgSOand evaporated. The residue is purified by chromatography on silica gelto yield the title compound, nmr (CDCl 50.88 (t, 3H), 1.77 (m, 2H), 3.77(s, 3H).

By following the procedure of Example 2 and utilizing the appropriateWittig reagent and compound of formula V then other compounds of formulaVI are prepared. Examples of such compounds of formula V are listed indicarboxylate, 45 dimethyl 2-formyl-3-ethylcyclopropane-1,l- Table Itogether with the appropriate Wrttrg reagent and dicarboxylate, compoundof formula V utilized for their preparation.

TABLE I Wittig reagent Compound oi )n zCO-(c) 3) Formula V All: (e) RCR3 Product: (Prefix listed below) eycIopropane-l,l-dicarboxylate C 3 2H CH3 Dimethyl trans-2-(3-oxo-1-pentenyl). CH3 2); H C H Diethyltrans-2-(3-0xo-1-octenyl). C H: (0 Hz) a H 0 H3 Dimethyltram-Z-(3-oxo-1-hepteny1) C H3 CH2) 5 H CH3 Dimethyltrans-2-(3-oxo-1-noneyl). C (C z) a H 0 H3 Dimethyltram-2-(3-oxo-l-decenyl) CH3 CH3CH=CH H CH3 Dimethyl trams-2-(3-0xo-1,5heptad1enyl) CH3 CH3 CH=C C H; H C H3 Dimethyltrans-2-(30x01,5-octad1enyl). CH: C H; CH=CH C H H CH3 Dimethyl tram-Z-(3-0xo-L5-n0nadlenyl) CH3 CH3CH=CH(CH3)3 H CH3 Dimethyltram-2-(3-oxo-1,5-decadrenyl). C CH: CH3 Dimethyltrans3-methyl-2-(3oxo-1-pentenyl). 0 Ha (0 Hz) a C H: 0 H3 Dimethyltrans-3-methyl-2-(3-oxo-1-hexenyl) CH3 (CH1): CH: CH3 Dimethyltran3-3-methyl-2-(3bx0-1-heptenyl). CH3 C 2) 4 CH: C H3 Dimethyltransa'i-methyl-2-(3pxo-1-octenyl) C H; (C H2) 5 CH3 CH3 Dimethyltrans-3-methyl-2-(3-oxo-1-nonenyl). C 2) 6 CH3 CH3 Dimethyltrans-3-methyl-2-(3oxo-1-deeenyl). CH3 CH CH=CH CH: 0 H3 Dimethyltramw'i-methyl-2(3-oxo-1,5-heptad1enyl). CH: C H3 CH=CHCH3 CH3 CH3Dimethyl trans-3-methyl-2-(3px0-1,fi-octadienyl) CH3 CH: C H=CH( CH3)CH3 CH3 Dimethyl trans-3-methyl-2-(3-oxo-l,5-nonadi enyl) C H: CH3CH=CH(CH3) 2 CH3 CH3 Dimethyl trans-3-methyl-2- (3'0X0)-1,5-d908d19f1l). 0H3 C H3 C 3H3 C H; Dimethyl tram-3-ethyl-2-(3-oxo-1-pentenyl) CH3 (C M03H; C311 Diethyl trans-3-ethyi-2-(3oxodoctenyl). C 2) s 03H; 0 HDimethyl trans-3-ethyl-2-(3-ox0-1-decenyl) C211 CH3CH=CH CzH3 CgH3Dlethyl trans-S-ethyl-2-(3-oxo-l,S-heptadrenyl). C2 5 CH3CH=CHC H3 C3H3C311 Dieth yl trans-3-ethyl-2-(3-oxo-l,5-octadieny1). C C 2): n-CaH7 CH3Dimethyl trans-.i-propyl-2-(3-oxo-1-hexenyl) C (C 1) 4 n- C3H1 C H3Dimethh yl trans-3-propyl-2-(3-oxo-1-octenyl) 2 (C M i-CaH7 02H: Diethyltrans-3-isopropyl-2-(3-oxo-l-nonenyl). C2H5 C zC H=C H( CH3), i-C3H1 CH3Dimethyl trans-B-ixopropyl-Z-(3-0x0-1,5-n0nedienyl) CzH3 CH CH=CH(CHn-C3H1 CH3 Dimethyl traws-3-propyl-Z-(3-oxo-1,5-decndienyl). C H3 CH2) 3AcOCH3 CH3 Dimethyl trans-3-(aeetoxymeth yl)-2-(3-oxo-1-heptenyl) CH3(CH AeOCH, CgHs Diethy l trans-3-(aeetoxymethyl)-2-(3-oxo-1-octcnyl), 7min. 730, 1,690, 1,670, 1,625

O 0 H3 (CH A00 CH3 CgHs Diethyltmns-3-(aeet0xymethyl)-2-(3-oxo-1-rlecenyl). CH3 CH3CH=CH A00 CH 0 H;Diethyl trans-3-(acetoxymethyD-2-(3-0x0-1,5'heptedienyl). 36 CH3 CHCH=CHCH AeOCH, C H DiethyltTans-3-(acetoxymethyl)-2-(3-oxo-1,5-0etadienyl).

EXAMPLE 37 1- Dimethyl amino) -1-octen-3-one A solution of dimethylamine(560 ml., 40% aqueous) is cooled to C. 1-Chloro-l-octen-3-one (192 g.)is added and the mixture stirred at room temperature for min. Thesolution is then saturated with potassium carbonate and extracted withether. The organic layer is washed 3 X with sat. sodium chloridesolution, dried over sodium sulfate, concentrated and distilled to givethe title compound, b.p. 94-96 C./ 0.2 mm.

In the same manner but replacing 1-chloro-1-octen-3- one with anequivalent amount of 1-chloro-1-penten-3- one, 1-chloro-1-hexen-3-one,l-chloro-l-hepten 3 one, l-chloro 1 nonen-3-one or1-chloro-1-decen-3-one, then 1- (dimethylamino -1-penten-3-one, 1-dimethylamino -1- hexen-B-one, l-(dimethylamino)-1-hepten-3-one, 1(dimethylamino)-1-nonen-3-one and 1 (dimethylamino-ldecen-3-one areobtained, respectively.

EXAMPLE 38 1,3-Decadien-5-one To a solution of Grignard reagent preparedfrom vinyl bromide (10.7 g.), and magnesium (2.43 g.) in drytetrahydrofuran (40 ml.) is added gradually a solution of1-(dimethylamino)-1-octen-3-one (16.9 g.), described in Example 37, indry tetrahydrofuran (20 ml.). The mixture is stirred and heated toreflux for 1 hr. The reaction mixture is cooled to room temperature,diluted with ether, washed with hydrochloric acid (10 ml.), followed bysaturated ammonium chloride solution. The ether extract is dried, andthe solvent is removed. The residue is chromatographed to yield thetitle compound,

A212? 260 nm. (e=17,050), 72?}, 1686, 1668 CHI-1.

In the same manner but replacing 1-(dimethylamino)- l-octen 3 one withan equivalent amount of l-(dimethylamino)-1-penten-3-one,l-(dimethylamino) 1 hexen- 3-one, 1-(dimethylamino)-1-hepten-3-one, 1(dimethylamino)-1-nonen-3-one or 1 (dimethyl-amino)-l-decen-3- one, then1,3-heptadien-5-one, 1,3 octadien-S-one, 1,3- nonadien 5 one,1,3-undecadien-5-one and 1,3-dodecadien-S- are obtained, respectively.

EXAMPLE 39 2- Dimethylamino -1-decyn-5-one A mixture of 1(dimethylamino)-1-octen-3-one (4.0 g.), described in Example 37, andlithiumacetylide-ethyleneamine (4.0 g.) in dry dioxane ml.) is stirredat room temperature for 45 min. The mixture is added to ice. The mixtureis extracted with ether. The extract is dried (Na SO and thenevaporated. The residue is distilled to afford the title compound, b.p.80-85 C.

In the same manner but replacing 1-(dimethylamino)- 1-octen-3-one withan equivalent amount of l-(dimethylamino)-1penten-3-one,'l-(dimethylamino) 1 hexen- 3-one, 1-(dimethylamino)-1-hepten-3-one, 1(dimethylamino)-1-nonen-3-one or 1-(dimethylamino)-1-decen-3- one,described in Example 37, then 2-(dimethylamino)-lheptyn-S-one,2-(dimethylamino)-1-octyn 5 one, 2-(dimethylamino)-1nonyn-5-one, 2(dimethylamino)-1-undecyn-S-one and Z-(dimethylamino)-1-dodecyn-5-oneare obtained, respectively.

EXAMPLE 1,3-Decadien-5-one To a solution of 2(dimethylamino)-1-decyn-5-one (2.2 g.), described in Example 39, inmethanol (20 ml.) p-toluenesulfonic acid (1 g.) is added. The solutionis allowed to stay at room temperature for 5 hr. then diluted withether. The organic layer is washed with water, dried (MgSO andevaporated to dryness. Chromatographic purification of the residue on 25g. silica gel with ether-hexane (1:4) affords 3-decen-l-yn-5-one.

A solution of the latter compound (1.93 g.) in hexane (20 ml.)containing quinoline (1 ml.) and Lindlar catalyst (100 mg.) ishydrogenated at room temperature and atmospheric pressure. After theabsorption of 296 ml. of hydrogen, the reaction mixture is filteredthrough diatomaceous earth, washed with 10% hydrochloric acid, then withwater, dried and the hexane evaporated to give the title compound,identical to the product of Example 38.

In the same manner but replacing 2-(dimethylamino)- l-decyn 5 one withan equivalent amount of 2 dimethylamino)-1-heptyn 5 one,2-(dimethylamino)-1- octyn 5 one, 2-(dimethylamino)-1-nonyn-5-one,2-(dimethylamino) 1 undecyn-S-one, or 2-(dimethylamino)-l-dodecyn-S-one, then 1,3-heptadien-5-one, 1,3-octadien- 5one,1,3-nonadien-5-one, 1,3-undecadien-5-one and 1,3- dodecadien-S-one areobtained, respectively.

EXAMPLE 41 Diethyl trans-2-(3-Oxo-1-octenyl)cyclopropane 1,1dicarboxylate[VI, R =H, R =C H and (c)=(CH To a solution ofdiethylbromomalonate (2.87 g.) in absolute ethanol (3 ml.) is addedsimultaneously sodium ethoxide (from 276 mg. sodium) in ethanol (6 ml.)and 1,3-decadien-5-one (1.9 g.), described in Example 40, in ethanol (3ml.). The sodium ethoxide is added over a period of 20 min. and thedienone over a period of 10 minutes. The mixture is stirred at 0 C. for3 hr., then at room temperature for 16 hr., acidified with 0.5 ml. ofacetic acid and the sodium bromide is separated by filtration and washedwith benzene. Evaporation of the solvent affords the amide product,which is subject to chromatography on 350 g. silica gel elution withether-hexane (1 :4) to give the title compound, n.m.r. (CDCl 6 0.88 (t,3H), 4.18 (q, 4H), 6.22 (s, 1H), 6.28 (s, 1H).

In the same manner but replacing 1,3-decadien-5-one with an equivalentamount of 1,3-heptadien-5-one, 1,3- octadien-S-one, 1,3 nonadien-S-one,1,3-undecadien-5- one or 1,3-dodecadien-5-one, then diethyltrans-2-(3-oxo- 1 pentenyl)cyclopropane 1,1 dicarboxylate, diethyltrans-2-(3-oxo-l-hexenyl)cyclopropane 1,1 dicarboxylate, diethyltrans-2-(3-oxo-1-heptenyl)-cyclopropane-1,1- dicarboxylate, diethyltrans-Z-(3-oxo-1-nonenyl) cyclopropane-l,l-dicarboxylate, and diethyltrans-2-(3-oxo-ldecenyl)-cyclopropane-1,l-dicarboxylate are obtainedrespectively.

Likewise the corresponding dimethyl and dipropyl esters of the abovecompounds of formula VI are obtained when diethylbromomalonate isreplaced by dimethyl or dipropyl bromomalonate, respectively, in theprocedure of this example.

EXAMPLE 42 Dimethyl trans-2-(3-Hydroxy 1 octenyl) cyclopropane-1,1-dicarboxylate [11, R =H, R =CH R =H and 2)4] A solution of 5.5 g. ofsodium borohydride in'50 ml. of ethanol is added to a solution of thecompound of formula VI, dimethyltrans-2-(3-oxo-l-octenyl)cyclopropane-l,l-dicarboxylate (35 g.),described in Example 2. After 15 min. at room temperature the mixture iscooled in ice and rendered neutral by the addition of acetic acid. Wateris added and the mixture extracted with ethylacetate. The extract wasdried (Na SO and then evaporated. The residue is purified bychromatography on silica gel to afford the title compound, NMR (CDClg),6 0.90 (t, 3H), 2.33 (1H), 3.73 (s, 3H), 4.05 (m, 1H).

By following the procedure of Example 42 and utilizing the appropriatecompound of formula VI then other compounds of formula H (R =H) areprepared. Examples of such compounds of formula II are listed in TableII. In each case the compound of formula VI used as 15 starting materialis noted by the Example in which it is prepared.

TABLE II N o. of example in which starting material Product: (Prefixlisted below) cyclo- Ex is prepared propane-1,1-dicarboxylate 43 3Dimethyl trans-2-(3-hydroxy-1-pentenyl) 44- 4 Diethyltrams-2-(3-hydroxy-1-octenyl).

45. 5 Dimethyl trims-2-(S-hydroxy-l-heptenyl) 46 6 Dimethyltra'ns-2-(3-hydroxyl-nonenyl) 47 7 Dimethyltrans-2-(3-hydroxy-1-decenyl).

48 8 Dimethyl trans-2-(3-hydroxy-1,5-heptadienyl).

49. 9 Dimethyl trans-il-(3-hydroxy-1,5-octadienyl) 50. 10 Dimcthyltrans-2-(3-hydroXy-1,5-nonadieny1) 51. 1 l Dimethyl trans-2-(3-hydroxy-l,S-decadienyl) 52. 12 Diniethyl trans-3-methyl-2 (3-hydroxy-lpenten yl)53- 13 Dimetli yl-trans-3-methyl-2-(3-hydroxy-1- hexenyl) 54- 14Dimethyl-trans-3-methyl-2-(3-hydroxy-1- h ept enyl) 55- 15Dimethyl-trans-3-methyl-2-(3-hydroxy-1- octenyl) 56 16Dimethyl-trans-3-mcthyl-2-(3-hydroxy-lnonenyl 57. 17Dimethyl-lransw'lmethyl-(B-hydroxy-ldecenyl) 58 18 Dimethylirans-3-methyl-2(3-hydroxy-1,5-

heptadienyl).

59 10 Dimethyl trans-3-methyl-2-(3-hydroxy-1,5- oetadienyl) 60. 20Dimethyl trans-{i-met hyl-2-(3-hydroxy-1,5 nonadienyl) G1 21 Dimethyltram3-methyl-2-(3-hydroxy-1 ,5- decadicnyl) 62 22 Dimethyllmns-3-ethyl-2-(3-hydroxy-1- pentenyl).

63. 23 Diethyl trans-3-cthyl-2-(3-hydroxy-1-octenyl) 64. 24 Dimethyltrans-3-ethyl-2-(3-hydroxy-1- decenyl) 65. 25 Diethyltrans-3-ethyl-2-(3-hydroxy-1,5-

hept adienyl) 66. 26 Diethyl trans-3-ethyl-2-(3-hydroxy-1,5-

octadienyl).

67. 27 Dimethyl trans-3-propyl-2-(3-hydroxy-1- hoxenyl) 68. 28 Dimethyltmns-3-pr0pyl-2-(3-hydroxy-1- octenyl) 69. 29 Diethyltrans-3-isopropyl-2-(3-hydroxy-1- nonen yl) 70- 30 Dimethyltrans-3-isopropyl-2-(3-hydroxy-l ,5-

nonadienyl) 71 31 Dimethyl trans-El-propyl-Z-(3-hydroxy-1,5-

decadienyl) 72- 32 Dimethyl trans3-(acetoxymethyD-2-(3- hydroxy-l-heptenyl) 73 33 Diethyl trans-B-(acetoxymethyl)-2-(3- hydroxy-l-octenyl) 7m. 3,600, 3,500, 1 ,730 cm..

74- 34 Diethyl irans-3-(acetoxymethyl) -2-(3-hydroxy- I-deeenyl).

75 35 Diethyl trans-3-(acetoxymethy1)-2-(3-hydrox y- 1,5-heptadieny1).

76- 36 Diethyl tram-3-(aeetcxymethyl)-2-(3-hydroxy- 1,5-octadienyl).

EXAMPLE 77 Dimethyl trans-2-{3-[(Tetrahydropyran-Z-yl)oxy]-l octenyllcyclopropane 1,1 dicarboxylate [II, R ZI-I, R =CH R=tetrahydropyran-2-yloxy and A solution of dimethyltrans-2-(3-hydroxy-1-octenyl)- cyclopropane-l,l-dicarboxylate (22.4 g.),described in Example 45, dihydropyran (80 ml., distilled over sodium)and p-toluenesulfonic acid monohydrate (300 mg.) is allowed to stand atroom temperature for 30 min. After adding a few ml. of 10% Na COsolution the mixture is extracted with ether. The ether extract iswashed with water, dried (Na SO and evaporated. Purification of theresidue by chromatography on silica gel gives the title compound.

In the same manner but using an equivalent amount of one of thecompounds of formula II (R =H), for example, the compounds listed inExamples 43 to 76, instead of dimethyltrans-2-(3-hydroxy-1-octenyl)cyclopropane- 1,1-dicarboxylate, then thecorresponding tetrapyrauyl ether compound of formula II (R=tetrahydropyranyl) is obtained, for example, the correspondingtetrahydropyranyl ether compounds of Examples 43 to 76, respectively.More specifically exemplified, in the same manner diethyl trans-3-(acetoxymethyl -2- 3-hydroxy- 1 -octenyl) 16cyclopropane-1,1-dicarboxylate (Example 73) gives diethyl trans-3-(acetoxymethyl -2-{3-[ (tetrahydropyran-Z-yl)oxy]-1-octenyl}cyclopropane-1,l-dicarboxylate,

1'31 40, 1720 cmf and dimethyltrans-3-methyl-2-(3-hydroxy-1,5-heptadienyl)cyclopropane-1,1-dicarboxylate(Example 58) gives dimethyl trans-2-{3-[ (tetrahydropyran-Z-yl oxy] l,S-heptadienyl}cyclopropane-1,1-dicarboxylate.

EXAMPLE 78 7-Hydroxy-5-heptynoic Acid (XII, p=3) By following theprocedure of A. I. Rachlin, et al., cited above, 6-chloro-2-hexyn-1-olis prepared by condensing propargyl alcohol tetrahydropyran-Z-yl etherand other dihaloalkane of formula VHI, 1-bromo-3-chloropropane, to give1-[(tetrahydropyran-Z-yl)oxy]6-chloro-2- hexyne, which is then convertedto the desired compound followed by hydrolysis in the presence ofsulfuric acid. The 6-chloro-2-hexyn-1-ol (280 g.) is dissolved inethanol (2.8 1.) then water (560 ml.) and potassium cyanide (290 g.) isadded and the mixture stirred and refluxed for 20 hr. Potassiumhydroxide (768 g.) and water (500 ml.) are added and the stirred mixturekept at reflux for an additional 20 hr. Methanol is evaporated and thewater phase is acidified with concentrated HCl and extracted with etherfor 2 days in a continuous liquid-liquid extractor. The ether extract isdried (Na SO and concentrated to give the title compound, nmr (CDCl 64.22 (m, 2H), 7.41 (broad, 2H).

EXAMPLE 79 Methyl 7-Bromo-5-heptynoate (XV, 1:3 and R=CH To a solutionof 7-hydroxy-5-heptynoic acid (88.2 g.), described in Example 78, inanhydrous ether (300 ml.) and pyridine (12 ml.) is added dropwisephosphorus tribromide (67.5 g.) at 10 C. The solution is stirred at roomtemperature for 30 min. then cooled at 5 C. and 10% HCl ml.) is addedslowly. The organic layer is washed with water and 10% sodium carbonate,dried (Na SO and concentrated. The residue is distilled under reducedpressure to give 7-bromo-5-heptynoic acid acid, b.p. 146 C., 0.8 mm.

The latter compound is esterified in the following manner. The lattercompound (156 g.) is dissolved in absolute methanol (1.5 1.).p-Toluenesulfonic acid (78 g.) is added to the solution which is thenheated at reflux for 2 hr. Thereafter the solvent is evaporated. Theresidue is dissolved in water and the aqueous solution extracted withbenzene. The extract is washed-with 10% Na CO and then water untilneutral, dried (Na SO and concentrated. The residue is distilled to givethe title compound, b.p. 70-80" C. 0.2 mm.

The corresponding ethyl or other lower alkyl esters of the lattercompound are likewise prepared according to the preceding esterificationprocedure by replacing methinol with ethanol or an appropriatecorresponding lower alkanol, respectively.

Alternatively, the procedure of this example may be reversed whereby7-hydroxy-5-heptynoic acid is first subjected to the esterificationprocedure with methanol and ptoluenesulfonic acid, followed by treatmentof the resulting hydroxy ester XIV (12:3 and R=CH with phosphorustribromide asd escribed herein.

By following serially the procedures of Examples 78 and 79 but using thedihaloalkanes of formula VIII, 1- bromo-Z-chloroethane or1-bromo-4-chlorobutane, instead of l-bromo-4-chloropropane, then methyl6-bromo-4-hexynoate and methyl 8-bromo-6-octaynoiate are obtained,respectively.

Furthermore, an equivalent amount of the correspondinga-iodo-w-chloroalkane used in place of the dihaloalkane of formula VIIin the serial application of the procedures of Examples 78 and 79 givesthe corresponding chloroester of the bromoester of formula XV; namely,

1 7 l-chloro-Z-iodoethane, 1-chloro-3-iodopropane andl-chloro4-iodobutane yield methyl 6-chloro-4-hexynoate, methyl7-chloro-5-heptynoate and methyl 8-chloro-6-octynoate, respectively.These latter methyl esters may be used in the manner described below forutilizing the bromoesters of formula XV.

EXAMPLE 80 Trimethyl 3-Heptyne-l,1,7-tricarboxylate (III; (a)=C:-C,p==3, R=CH and R CH Dimethyl malonate (39.6 g., 0.3 mole) is addedslowly with cooling and stirring to a solution of 6.9 g. (0.3 atom) ofsodium dissolved in 100 ml. of absolute methanol and the mixture stirredfor 15 min. The bromoester of formula XV, methyl 7-bromo-5-heptynoate(65.7 g., 0.3 mole), described in Example 79, is added dropwise. Themixture is heated at reflux for 1 hr., cooled and diluted with water.The mixture is extracted with ether. The ether extracts are dried (Na SOand concentrated. The residue is distilled under reduced pressure, togive the title compound, b.p. 153 C./0.4 mm., nmr (CDCl 6 3.69, 3.78.

In the same manner but replacing methyl 7-br0mo-5- heptynoate with anequivalent amount of methyl 6-bromo- 4-hexynoate or methyl8-bromo-6-octynoate, trimethyl 3- hexyne-l,1,6-tricarboxylate andtrimethyl 3-octyne-1,1,8- tricarboxylate are obtained, respectively.

In the same manner but replacing methyl 7-bromo-5- heptynoate with anequivalent amount of methyl 6-bromo- 4-hexenoate, methyl7-bromo-5-heptenoate, methyl 8-bromo-fi-octenoate, methyl6-bromohexenoate, methyl 7-bro moheptanoate, or methyl 8-bromooctanoate,trimethyl 3- hexene-1,1,6-tricarboxylate, trimethyl3-heptene-1,1,7-trimethyl 3-octene 1,1,8 tricarboxylate, trimethylhexane- 1,l,6-tricarboxylate, trimethyl heptane-1,1,7-tricarboxylate andtrimethyl octane-1,1,8-tricarboxylate are obtained, respectively.

By using the corresponding ethyl or other lower alkyl ester analogs ofthe methyl ester starting materials noted above, the corresponding ethylor other lower alkyl esters of the methyl ester products, noted above,are obtained.

EXAMPLE 81 Trimethyl cis-3-Heptene-1,1,7-tricarboxylate (III, (a)=CH=CH, 11:3, R=CH and R =CH Trimethyl 3-heptyne-1,1,7-tricarboxylate(30.5 g.), described in Example 80, is hydrogenated in the presence of1.0 g. of Lindlar catalyst [Org. Cyn., 46, 89 1966)] in a solution of100 ml. of ethyl acetate and 1000 ml. of hexane. After 4 hr. andabsorption of 740 ml. of hydrogenation another 1.0 g. of catalyst isadded. After a further 8 hr. an additional 880 ml. of hydrogen isabsorbed. No further absorption of hydrogen is observed. After filteringthe filtrate is concentrated. The residue is distilled under reducedpressure. The title compound has b.p. 140-150 C./0.7 mm., nmr (CD61 a3.55 (1H), 5.41 (m. 2H), identical to the same compound described inExample 80.

In the same manner but using trimethyl 3-hexyne-1,l,6- tricarboxylate ortrimethyl 3-octyne-1,1,8-tricarboxylate, trimethyl3-hexene-1,1,6-tricarboxylate and trimethyl 3- 18 EXAMPLE s2 Dimethylcis, trans 3 (6-Carbomethoxy-2-hexenyl)-4- (3-hydroxy-1-octenyl)-2-oxo1,3 cyclopentanedicarboxylate (IVa; (a)=CH=CH, p=3, (c)=(CH R, R and R=CH and R and R"=H) Procedure A [using compound II (R =tetrahydropyran-2-yl) To a mixture of the compound of formula H, dimethyl trans-2-{3-[(tetrahydropyran-Z-yl) oxy] -1-octenyl}cyclopropane-1,l-dicarboxylate(20.4 g.), described in Example 77, and the compound of formula III,trimethyl cis-3-heptene-1,1,7-tricarboxylate (15.08 g.), described inExample 81, a solution of 1.27 g. of sodium in 50 ml. of methanol isadded at room temperature. The methanol is removed under slightlyreduced pressure. The residue is heated at 135-140 C. for 1 hr. whilekeeping a slightly reduced pressure in the reaction flask. SaturatedNaCl solution is added and the mixture rendered neutral with aceticacid. The mixture is extracted with ether. The extract is dried (Na SOand concentrated. Chromatography of the residue on silica gel yieldsdimethyl cis, trans-3-(6-carbomethoxy-2-hexenyl)-4-{3[tetrahydropyran-2-yl)oxy]-1-octenyl}-1,3 cyclopentanedicarboxylate, nmr(CD01 a 0.90 (t, 1: 6, 3H), 3.68-3.78 (3H), 3.20 (2H), 4.20 (1H).

A solution of the latter compound (10.5 g.) in 80 ml. of methanol-water(9:1) and 1.0 g. of p-toluenesulfonic acid monohydrate is left at roomtemperature for 15 min. and then rendered neutral with aqueous NaHCO Themethanol is evaporated and after addition of saturated NaCl, the mixtureis extracted with ether. The ether layer is dried (Na SO Evaporation ofthe solvent gives a residue, which on purification by chromatography onsilica gel affords the title compound, nmr (CDCI 0.90 (t, J=5, 3H),3.68, 3.74 and 3.78 (3H), 4.15 (1H), 5.1-5.8 (m, 1H).

Procedure B [using compound II (R =H)]: Sodium methoxide [from 0.5 g.(0.22 atom) of sodium and 30 ml. of absolute methanol] is added at roomtemperature to a mixture of 5.6 g. (0.02 mole) of the compound offormula II, dimethyltrans-2-(3-hydroxy-l-octenyl)cyclopropane-1,1-dicarboxylate, describedin Example 42, and 5.4 g. (0.02 mole) of the compound of formula III,trimethyl cis-3-heptene-1,1,7-tricarboxylate, described in Example 81,in 10 ml. of absolute methanol. After refluxing for 2 hr. the methanolis removed at reduced pressure and the residue adjusted to pH 6 withacetic acid. The mixture is extracted with ether. The ether extract isworked up in the same manner as described for the ether extract inprocedure A of this example. In this manner the title compound isobtained, identical to the product of procedure A.

By following the procedures A or B of Example 82 and using theappropriate compounds of formulae II and III as starting materials,other cyclopentanonetriesters of formulae IVa or IVb are prepared.Examples of such compounds of formula IV are listed in Tables III andH121 together with the requisite starting materials. It is to be notedthat when procedure A is used the requisite starting material of formulaII is the corresponding tetrahydropyran-Z-yl ether derivative of thecompound of formula II noted therein; the tetrahydropyran-2-yl etherbeing prepared by following the procedure described in Example 77.Preparation of the starting materials of formula HI,

O t Y identical to the Same i.e. triesters of formula III, is describedin Examples pounds described in Example 80, are obtained. and 81.

TABLE III No. of example in which starting Starting material of materialof Formula III Formula II is described (a) p R and R Product:(Preflzltsted below)-2oxo-1,3-eyclopentanedicarboxylate 43 %E% 2 CHDimethyl trans-3-(5-carbomethoxy-2-pentynyl)-4-(3-hydroxy-1-pentenyl).44 3 CzHs Diethyltrans-I-l-(6-carboethoxy-2-hexynyl)-4-(3-hydroxy-1-octenyl), 1 3 3,450,1,737,

1,225 emf 45 %E% 4 CH: Dimethyltmns-3-(7-earbomethoxy-2heptynyl)-4-(3-hydroxy-l-heptenyl). 46 %H=%H 2CH3 Dimethylcis,tram-3-(5-carbomethoxy-2-pentenyl)-4-(3-hydroxy-1-nonenyl). 47 %H=%H3 CH Dimethy1cz's,tram--(6-carbomethoxy-2-hexenyl)-4-(3-hydroxy-1-decenyl). 43 %H=% 4 CHDimethylcis,trans-3-(7-carbomethoxy-2-heptenyl)-4-(3-hydroxy-1,5-heptadienyl).

TABLE TIL-Continued No. of example in which starting Starting materialof material of Formula III Formula II is described (a) p R and RProduct: (Prefix listed below)-xo-1,3-cyclopentanedicarboxylatc 49CHQCHZ 2 CH3 Dimethyltmns3-(5-carbomcthoxypentyl)-4-(3-hydroxy-1,5-octadienyl). 50 CHzCI-Iz 3CH Dimethyl tran:1-3-(fi-carhomethoxyhexyl)-4 (3hydroxy-1,5-nonadienyl).51 4 CH Dimethyltrans-3(7-carbomethoxyheptyl)-4-(3-hydroxy-1,fi-decadienyl). 52 2 CH3Dimethyltrans-3-(5-carb0rneth0xy2-pentyny1)-4-(3-hydroxy-1-pentenyl)-5-methy1.53 3 CH: Dimethyltmns-3(G-carbomethoxy-2-hexynyl)-4-(3-hydroxy-1-hexenyl)-5-methyl. 54 4CH Dimethyltrans-3-(7-earbomethoxy-2-heptynyl)-4-(3-hydloxy-l-heptenyl)-5-methyl.55 2 CH3 Dimethyl cz's,tram-3-(5carhomethoxy-Z-pcntenyl)-4-(3-hydroxy-1-octenyl)-5-methyl. 56 3CH3 Dimethyl cis,trans-3(G-carbomethoxy-Z-hexenyl)4(3-hydroxy-1-nonenyl)-5-methyl. 57 4CH3 Dimcthyl ci's,trans-3-(7-carbomethoxy-2-heptenyl)-4(3-hydroxy-1-decenyl)-5-methyl. 582 CH; Dimethyl trans, cis(5-carbomethoxypentyl)-4-(3-hydroxy-1,S-heptadicnyl)-5-methyl. 59 3 CHDimcthyl trans, c(G-carbomethoxyhexyl)-4-(3-hydr0xy-1,5-octadienyl)-5-rnethyl. 60 4 CH3Dimethy. trans, czs(7-carbo1ncthoxyheptyl)-4-(3-hydr0xy-1,5-nonadienyl)-5-methyl. 61 2 CH;Dimethyl trans, cis-(5carbornethoxy-Z-pentynyl)-4-(3-hydroxy-1,5-decad1enyl)-5-mcthyl. 6 3CH3 Dimcthyl trans, cis--(6-carbomcthoxy-2-hexynyl)-4-(3-hydroxy-1-pentenyl)-5-ethyl. 63 4 C 11Diethyltrans-1%(7-carboethoxy-2-heptynyD-4(3-hydroxy-l-octenyl)-5-ethyl. 64 2CH3 Diinethyl cz's,tTans-3-(5-earbometh0xy-2-pentenyD-4-(S-hydroxy-l-decenyl)-5-cthyl. 65 3C2H5 Dicthyl 01's, trans,eta-3-t6-carbocthoxy-2-hexenyl)4-(3-hydroxy-1,S-heptad enyD-S-ethyl. G64 C H Dicthyl cis, trans,ctr-3-(7-carh0ethoxy-Z-heptenyl)-4-(3l1ydroxy-1,5-octad1enyl)-5-ethyl.67 2 CH3 Dimethyltrans-3-(5-carbomethoxypentyl)4-(3-hydroxy-1-hexenyl)-5-propyl. 68 3 CH;Dimethyl trans-3-((i-carbomcthoxyhexyl)4(3hydroxy-1-octcnyl):5-propyl.69 4 0 H; Diethyltrans3-(7-carboethoxyheptyl)-4-(3-hydr0xy-1-n0i1enyl)-5-is0propyl. 70 2CH3 Dimethyl trans, cis 3-(5-carbomethoxy-2-pentynyl)4-(3-11ydroxy-1,5-nonadienyl)-5-ls0propyl 71 3 CH3 Dimethyl trans,sis-3-(G-carbomethoxy-2hexynyl)4(3-hydroxy-1,EJ-decadienyl)-5-propyl.

TABLE Illa N0. of example in which start- Starting material ing materialof of formula III formula II in which start- Starting material ingmaterial of of formula III formula II Ex. is described (a) p R and R 4Product: (Prefix listedbelow)-5-(hydroxyn1cthyl)-2-oxo-1-cyclopentanecarboxlyic acid 'y-lactone112.... 72 C E C 4 CH3tm'ns-(i-carbomethoxy-3-(7-carbomethoxy-Z-heptynyl)-4-(3-hydroxy-1-heptenyl).113.... 73 CH CH; 3 OzHst1am-3-carboethoxy-3-(G-carboethoxyhexyl)4-(3-hydroxyl-1-octeyl), g3,500, 1,770, 1,730

emf. 114 74 CH=CH 3 CzHsci's,trans-3-carboethoxy-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-1-deceny1)115...- 75 CHzCHz 3 CzHs trans,cis 3-carboethoxy-3(6carboeth0xyhexyl)-4(3-hydroxy-1,S-heptaddenyl). 116.-.. 76 CHzCHz 4 C 11trans,cis-3-carboethoxy-S-(7-carboethoxyheptyl)-4-(B-hydroxy-l,fi-octadicnyl)-EXAMPLE 117 TABLE IV-Continued trans, cis 7 -[2 (3Hydroxy-l-octenyl)-5-oxocycl0 pentyl] 5 heptenoic lACld (I; (a)=CH=CH,p=3,

No. of example in which cyclopcntanonetriester of Formula (C)=(CH2)4 andR, R1 and RZZH) 35 Ex. IV is prepared Product The cyclopentanonetriesterof formula IV, dimethyl o 5-oxocyclopentyl]liexanoic acid. cis,trans 3(6 carbomethoxy-Z-hexenyl)-4-(3-hydr0xy- "gtfi gt iifglfifi111122132423?l-octenyl) 2 oxo-1,3-cycloperitanedicarboxylate (11.2 126... 01 trans,c1's,ris-8-[2-(3 hydroxy-1, 5idccadienyl)- g), descrihed in Example82, is heated to reflux for 1 hr. 92 t7 f gfgffigfggggll o fia r cg gg.3 methy1 5 in a solution of sodium hydroxide (13.4 g.) in 80 ml. 40 m 9oxoc cio i it ii-i-h ynoic 1 mg. h 1 of water and 110 ml. of methanol.'lthe mixture is cooled, 3 at y ad usted to pH 5 with 2 N HCl, dilutedwith saturated 4 s y fi pt ylg vt ylsodium chloride solution andextracted with ether. The 95 fggf fiitffif i fifg tfiliii it etherextract is dried (Na SO and concentrated to yield 45 131 96 t 09yg p tylfig g g d 3 m m 1 the title compound as a mixture of C epimers is sepggggi g fi mgflfifi in, e yarated by silica gel chromatography usinghexane: ehloro- 97 -1 -(3- y yc y yl- 5-oxocyclopentyll-G-octenoic acid.form. acetic acid. 10.20z1. The less polar ep1mer 1S des- 93 mm,i3-6.[2-(3.hydroxy-1 fi-heptadienyn-a. methyl-S-oxocyolopentyflhexanoicacid. lgnated ep1mer nmr (CDC13) 51 05 J 134.-- 00trans,cia-7-[2-(3-hydroxy-1,5-octadicnyD-3- 4.2 .0 (1H), 1 33-5.78 6.38The more polar 50 mcthyl-Somcyclopentyl]heptanoic acid. ep1mer 18designated ep1mer B, nmr (CDCI 61.05 (t, t i

I 3-mcthyl-5cxocylcopentyl1octanoic acid. 1:5, 3H), 4.18 (1H), 5.30-5.77(1H), 6.74 (2H). 136... 101trams,cis-G-[Z-(El-hydroxy-lfi-dgcadicnyK-fii n1cthyl-5-oxocyclopenty-4- exynoic aci By fOllO\V1I1g the procedure of Example 117 and using137 102 dmxy 1 pemeny1) 3 the appropriate cyclopentanonetriester offormula IV, for oxocyclopentyl]-5-licptyn0ic acid. example thosedescribed in Examples 83 to 116, then r 103 P i 1 5.OXOCYCIOIJOHLYI]-6-0t1tyn010 acid. other compounds of formula I in whichR and R are 139--- 104 trans,amt-[2-(3-hydroXy-1-decenyl)-3-ethyl-5-oxocyclopentyll i-hexenoic acid. hydrogen are ohtained. Examples of suchcompounds of 14m 105 mmm,Ci8 7 [2 (3 hydrOXy 1v5 hepmdicnyl) formula Iare listed in Table IV together with the req-3-ethyl-5-oxoeyclopentyl1-5-hcpten0ic acid. uisitecyclopentanonetriester starting material, the latter 1063-ethyl-5-oxocyelopentyl]-6-ootenoic acid. compound being noted by theexample describing its 142--- 107tram-6[2-(3-hydroxy-1-hexcnyl)-3-propyl-5- preparation 60oxocyclopentyflhexanoie acid.

143. 108 trans-7-[2-(3-hydr0xy-1-octenyl)-3-propyl-5- TABLE IVoxocyclopentyflheptanoic acid. of example 144. 109tram-8-[2-(3-hydroxy-1-n9nenyl)-3-isopropylin which cyclmoxoeyclopentyfloctanmc acid.

penmnonetm 145. 110 trim a, c1s-6-[2-(3-hydro1y-1, 5-nonadienyl)-3-ester of Formula isopropyl-5-oxocyclopentyl]-4-hexyn0ic acid. EL lvisprepared Product 5 146... 111trans,cis-7-[2-(3-hydroxyl-l,5-decadienyl)-3:-

propyl-5-oxocyclopentyl]-5-heptyno1c acid. 118 83trans-G-[2;(3.hydroxy-l-pentenyl)-5-oxocyclo- 147. 112trims-842-(3-hydroxy-1-heptenyl)-3-(hydroxyp py r' y fi methyl)-5oxocyclopentyll4i-octyn0ic acid. 119 8 -W-{ y y- -octeny1)-5 ox cyg1o-148. 113 tram-7-[2-(3-hydroxy-1-0ctenyl -3-(hydroxypentyl]-c-- heptynoicacid, 'YmBX mm 3,445 and methyl)-5-oxocyclopcntyl]heptanolc acid,

,73 7... film 3,4003,600, 1710 c.m.- 120-.- 85 z fili gfiygmggggp y cy70 149.-- 114 tram,sis-H2-(3-hydroxy-1-dccenyl)-3-(hy- 121 86 irtm s,tcz'iiilji-tii-hydroxygi-non euyl)-5-oxccyclogfiiymethyl)SamayGlOpBntyn5.heptenoic pen y exenoic aci 15() 1 .2. 122-.. 87 tram,cis-1-[2-(3-hydroxy-l-decenyl)5-oxocycl0- iii?iii)gmah, gffi w ifgggififig pentxl] he tennic acid. mnoic acid 1 88 y y: -h p y 151---116 tra-ns, cis-8-[2-3-hydroxy-1, 5-octadienyD-3,fi-oxocyclopcntyl]-6-octenoic acid.(hydroyymethyl).5.oxocyclopent,y]]octa- 124..- 89 trons, C18,czs-fi-[2-(3-hydroxy-1,5-octadicnyl)- 75 mic acid 21 IEXAMIPIJE 152Methyl trans,cis 7 [2 (3 hydroxy-l-octenyl)-5-oxocyclopentyl] 5heptenoate (I; (a)=CH=CH, p=3, (b)=CH=CH, (c)=(CH R=CH and R and R H)The compound of formula I, trans,cis 7 [2-(3-hydroxy 1 octenyl) 5oxocyclopentyl] 5 heptenoic acid (16.0 g.), described in Example 117, isdissolved in 150 ml. of absolute methanol. Perchloric acid (5 to 10drops) is added to the solution which is kept at room temperature for 2hrs. Thereafter the mixture is concentrated. The residue is diluted withwater and shaken with ether. The ether layer is washed with 10% Na COand then water until neutral, dried (MgSO and concentrated to yield thetitle compound,

755,9 1705 emf.

In the same manner but using the appropriate choice of the compound offormula I and lower alkanol, then other corresponding esters of formulaI (R: lower alkyl) are prepared. For example, the choice oftrans-8-[2-(3- hydroxy 1 heptenyl) 5 oxocyclopentyl] -6-octynoic acid(Example 120) and ethanol, instead of the compound of formula I andmethanol in the procedure of this example gives ethyl trans 8 [2 (3hydroxy-1-heptenyl)- 5 oxocyclopentyl] -6 octynoate. Similarly thechoice of trans 7 [2 (3 hydroxy 1 octenyl)-3-(hydroxymethyl) 5oxocyclopentyl]heptanoic acid (Example 113) and methanol gives methyltrans 7 [2-(3-hydroxy- 'l-octenyl) 3(hydroxymethyl)-5-oxocyclopentyl]heptanoate,

721:. 3420, 1730 cur- EXAMPLE 153 Methyl trans,cis-7-[2-(3-acetoxy-1-octenyl)-5- oxocyclopentyl] -5hepten0ate A solution ofthe compound of formula I, methyl trans,cis-7-[2-(3hydroxy-l-octenyl)-5-oxocyclopentyl]- S-heptenoate (5 g.), described inExample 151, in 50 ml. of pyridine and 50 ml. of acetic anhydride isstirred at room temperature for 4 hrs. The solution is diluted withice-water and extracted with ether. The ether is washed with 10% H 80water 10% Na CO and water, dried (Na S and evaporated to give the titlecompound.

In the same manner but using the appropriate choice of compound offormula I (R =H) and lower alkanoic anhydride, then other compounds offormula I (R=lower alkanoyl and if R is CH OR then R is lower alkanoyl)are prepared. For example the choice of trans-8-[2-(3- hydroxy 1nonenyl)-3-isopropyl oxocyclopentyl] octanoic acid (Example 144) andpropionic anhydride instead of the compound of formula I and aceticanhydride noted in the procedure of this Example, givetrans-S-[2-(3-propionoxy-l-nonenyl) 3 isopropyl-5-oxocyclopentyl1octanoic acid. Similarly, ethyl trans-8-[2-(3-hydroxy-1-heptenyl) 5 oxocyclopentyl]-6-octynoate (see Example 151)and butyric anhydride gives ethyl trans-8-[2-(3-butyryloxy 1 heptenyl) 5oxocyclopentyl1-6-octynoate.

We claim: 1. A process for preparing a compound of formula ICH=--(a)-(CH, ,0 o o R (b)CH(c)CHa R1 R I in which (a) is CHgCHz, cisCH=CH or CEC, p is an integer from 2 to 4, (b) is trans CH=CH, (c) iseither (CI-I wherein q is an integer from 1 to 6 or cis CI-I CH=CH(CHwherein r is an integer from 0 to 3,

22 R and R is each hydrogen and R is hydrogen, lower alkyl or CH ORwherein R is hydrogen which comprises subjecting a compound of formulaII in which R is hydrogen, lower alkyl or CH OR in which R is loweralkanoyl, R is lower alkyl, R is hydrogen or tetrahydropyran-Z-yl and(c) is as defined herein to a base catalyzed condensation at atemperature of to C. for 30 minutes to three hours in the presence of,as the base, an alkali metal alkoxide or an alkali metal hydroxide withapproximately an equimolar amount of a triester of formula III CHCHI(a)(CHI)pCO OR COOR III in which R and R are lower alkyl and (a) and pare as defined herein to yield the corresponding cyclopentanonetriesterselected from the group consisting of formula Na and formula IVb inwhich (a), (c), p, R R and R are as defined herein, R is lower alkyl andR is hydrogen or lower alkyl, said cyclopentanonetriester of formula IVabeing obtained when R of the compound of formula II is hydrogen or loweralkyl and said cyclopentanonetriester of formula IVb being obtained whenR of the compound of formula H is CH OR in which R is lower alkanoyl; inthe instance when R of the cyclopentanonetriester istetrahydropyran-Z-yl subjecting the cyclopentanonetriester to treatmentwith an acid in an inert solvent in the presence of water to remove thetetrahydropyran-Z-yl protecting group to obtain the correspondingcyclopentanonetriester in which R is hydrogen, and thereafter treatingthe instant cyclopentanonetriester intermediate with an alkali metalhydroxide to give the corresponding compound of formula I in which R andR are hydrogen and R is hydrogen, lower alkyl or CH OR wherein R ishydrogen.

Z. A process as claimed in Claim 1 in which the com pound of formula IIR 000 COOR in which (c) is either (CH wherein q is an integer from 1 to6 or cis CH CH=CH(CH wherein r is an integer from 0 to 3, R is hydrogen,lower alkyl or CH OR in which R is lower alkanoyl, R is lower alkyl,

23 R is hydrogen or tetrahydropyran-Z-yl is prepared by treating analdehyde of formula RAOOC COOR R CHO V in which R is hydrogen, loweralkyl or CI-I OR in which R is lower alkanoyl and R is lower alkyl, withan ylid prepared from a Wittig reagent of formula in which (c) is asdefined herein and Alk is an alkyl containing one to three carbon atoms,to yield the compound formula VI R C COOR IR2 CO(c)-CH; VI

in which (c), R and R are as defined herein, reducing the lattercompound with an alkali metal borohydride to obtain the correspondingcompounds of formula II in which R is hydrogen, thereafter and ifdesired treating the latter compound with dihydropyran in the presenceof an acid to give the corresponding compound of formula II in which Ris tetrahydropyran-Z-yl.

3. A process as claimed in Claim 1 in which the compound of formula II R00 C COOR in which n is as defined herein, treating the latter compoundwith a di(lower) alkyl bromomalonate in the presence of an alkali metallower alkoxide to yield the compound formula VI R2 C 0- (e) -CH; VI inwhich (c), R and R are as defined herein, reducing the latter compoundwith an alkali metal borohydride to obtain the corresponding compoundsof formula II in which R is hydrogen, thereafter and if desired treatingthe latter compound with dihydropyran in the presence of an acid to givethe corresponding compound of formula II in which R istetrahydropyran-Z-yl.

4. A process as claimed in Claim 1 in which the compound of formula II R000 COOR R II in which (c) is (CH wherein q is an integer from 1 to 6, Ris hydrogen, R is lower alkyl, R is hydrogen or tetrahydropyran-Z-yl isprepared by treating a chlorovinyl ketone of formula ClCH=CHCO(CH CH inwhich n is an integer from 1 to 6 with a di(lower)alkylamine to give thecorresponding di(lower)alkylaminovinyl ketone, treating the lattercompound with lithium acetylide or an acetylene Grignard reagent toobtain a compound of formula (lower alkyl) NCH(CECH)CH CO(CH ),,CH inwhich n is as defined herein, treating the latter compound with an acidto give the corresponding alkenynone derivative, hydrogenating thelatter derivative in the presence of Lindlar catalyst to give thecorresponding dienone of formula CH =CHCH==CHCO(CH ),,CH in which n isas defined herein, treating the dienone with a di(lower) alkylbromomalonate in the presence of an alkali metal lower alkoxide to yieldthe compound formula VI in which (c), R and R are as defined herein,reducing the latter compound with an alkali metal borohydride to obtainthe corresponding compounds of formula II in which R is hydrogen,thereafter and if desired treating the latter compound with dihydropyranin the presence of an acid to give the corresponding compound of formulaII in which R is tetrahydropyran-Z-yl.

5. The process according to claim 1 wherein the compound of formula I inwhich R and R are hydrogen and R is hydrogen, lower alkyl or CH ORwherein R is hydrogen is esterified with a lower alkanol in the presenceof an acid to give the corresponding compound of formula I in which R islower alkyl.

6. The process according to claim 1 wherein the compound of formula I inwhich R and R are hydrogen and R is hydrogen, lower alkyl or CH ORwherein R is hydrogen is acylated by treatment with a lower alkanoicanhydride or lower alkanoic acid chloride to give the correspondingcompound of formula I in which R is hydrogen, R is lower alkanoyl and Ris hydrogen, lower alkyl or CH OR wherein R is lower alkanoyl.

7. The process according to claim 5 wherein the compound of formula I inwhich R is lower alkyl, R is hydrogen and R is hydrogen, lower alkyl orCH OR wherein R is hydrogen is acylated by treatment with a loweralkanoic anhydride or lower alkanoic acid chloride to give thecorresponding compound of formula I in which R is alkyl, R is loweralkanoyl and R is hydrogen, lower alkyl or CH OR wherein R is loweralkanoyl, R and R being the same.

8. The process of claim 1 in which R and R each are hydrogen.

9. The process of claim 1 in which R and R each are lower alkyl.

10. The process of claim 1 wherein R as defined in connection withformula II, is lower alkanoyl and R as defined in connection withformula I, is hydrogen.

References Cited UNITED STATES PATENTS 3,711,528 1/1973 Beal 260468OTHER REFERENCES March: Organic Reaction Mechanisms, pp. 477-81 (1968).

ROBERT GERSTL, Primary Examiner US. Cl. X.R.

260240 R, 343.3, 345.4, 410.4 R, 413, 468 H, 485 R, 488 R, 514 D, 584 A;424305, 317

1. A PROCESS FOR PREPARING A COMPOUND OF FORMULA I